Gene Regulation and Cell Proliferation Program Program Leader: David L. Spector Program Co-leader: Christopher R. Vakoc Project Summary Alterations in the regulation of gene expression and promiscuous entry into the cell cycle are defining characteristics of human cancer cells. The Gene Regulation and Cell Proliferation Program (GR) represents an interdisciplinary program with the central aim focused on understanding the regulation of gene expression and cell proliferation in cancer cells. The program has three main focus areas: (1) RNA Biology, (2) Cancer Epigenetics, and (3) Cell Proliferation. Research in this Program over the past five years has produced major advances in our understanding of cancer promoting pathways and has led to the discovery of novel therapeutic strategies now under investigation in, or moving toward, human clinical trials. In the area of RNA biology, researchers in the GR Program have shown that machineries that regulate alternative pre-mRNA splicing reactions include a major class of oncoproteins in human breast and skin cancers. In addition, long non-coding RNAs have been causally linked to the differentiation and metastatic programs in breast cancer, thus motivating the evaluation of anti-sense oligonucleotide (ASO)-based therapeutics in pre-clinical models and in human clinical trials. Researchers investigating small RNA pathways have obtained insight into how cancer cells communicate with their microenvironment using exosomes and evade sensitivity to kinase-targeted therapeutics. An epigenetics focus of this program has led to the discovery that hematological malignancies exploit bromodomain-containing proteins to sustain oncogenic enhancer landscapes. This has led to a rationale to target specific bromodomains in cancer, an approach that is now under investigation in ealy stage clinical trials. Epigenomic profiling of mammary gland cell types is also revealing how a woman's risk for developing breast cancer can be modulated by transient signaling events during pregnancy. Studies in the area of DNA replication are focused on the mechanisms of origin recognition proteins and replicative DNA helicases, including those utilized by tumor-causing papillomaviruses. Technology development continues to be a major focus of the GR program. A novel CRISPR-based functional genomics strategy is revealing core gene regulatory circuitries that sustain the cancer cell state and is also identifying strategies to bolster blood stem cell self-renewal. High throughput screening of ASOs targeting long non-coding RNAs is leading to the identification of targetable vulnerabilites in breast cancers. A continued effort that balances basic research into molecular mechanisms with therapeutic development will lead to continued synergies among members of the Program that is fostered by the Cancer Center. Since 9/1/10, the GR Program published 126 cancer-related research articles, 30 (24%) involved multiple Cancer Center members; 11 (9%) from intra-programmatic collaborations and 25 (20%) from inter-programmatic collaborations. As of 8/1/15, scientists in the GR Program held $3.6 million of direct costs secured from NCI, other peer reviewed and non-peer reviewed, cancer-related research support. Of this, $3.2 million was from NCI and other peer reviewed cancer-related funding sources.